The present invention relates to compounds according to the general formula (I), with the definitions of the substituents X, R1 and R2 given below in the text, as well as their physiologically acceptable salts, methods for producing these compounds and their therapeutic use as pharmaceuticals.
These compounds are known as kinase inhibitors, and in particular, inhibitors of the glycogen synthase kinase-3β (kinase GSK-3β)
It is known from the literature that in the case of metabolic diseases such as diabetes or neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis, there is a connection between the therapy of said diseases and the inhibition of GSK-3β or the phosphorylation of the tau-protein (S. E. Nikoulina. Diabetes 51, 2190-2198, 2002; Henrikson. Am. J. Physiol. 284, E892-900, 2003). There are a number of compounds and pharmaceuticals that are already employed in the treatment of said diseases, in which the compounds interfere at different places within the biochemical processes that causes the respective disease. However, there is only a very limited number of compounds known until now, which effectively inhibit glycogen synthase kinase GSK-3β.
WO 04/046117 discloses a number of pyridazinone derivatives, which can be employed for the inhibition of GSK-3β. They differ from the compounds of the present invention in the substitution of the pyridazinone cycle, since at position 4 of the ring there is an amido group substituent instead of a heteroaryl substituent such as pyrrole or indole.
International Application PCT-EP 05/002179 also discloses pyridazinone derivatives that are useful in the inhibition of GSK-3β. In contrast to the compounds of the present invention, those compounds are substituted at position 4 of the pyridazinone cycle by a benzimidazole group. U.S. Patent Appln. 2002/0119963 to Sanner et. al. discloses imidazole derivatives having activity for inhibiting the kinases CDK5, CDK2 and GSK-3. The imidazole derivatives are substituted via the first nitrogen atom, among others, with a 3-8-membered hydrocyclelalkyl or a 5-14-membered hydroaryl group, but a pyridazinone group is not explicitly disclosed therein. Additionally, the imidazole derivative is substituted with an amino group, which is further substituted with a carboxyl group. Therefore, it is evident, that the pyridazinone derivatives of the present invention are not disclosed by U.S. Patent Appln. No 2002/0119963 to Sanner et. al. Compounds as those explicitly disclosed by US-A 2002/0119963 are not a subject of the present invention.
Furthermore, there are many pyridazinone derivatives described in literature, which differ from those of the present invention due to a different substitution pattern within the molecule and (partially) different indications.
WO 03/059891 discloses pyridazinone derivatives that are useful for treating diseases and conditions caused or exacerbated by unregulated p 38 MAP Kinase activity and/or TNF activity. The compounds described therein can be used, for example, for the treatment of inflammatory conditions, diabetes, Alzheimer's disease or cancer. They differ from the compounds of the present invention in the substitution of the pyridazinone cycle, since the nitrogen at position 2 of the cycle is mostly substituted with alky, aryl or heteroaryl and at position 4 of the cycle there is no heteroaryl group (such as pyrrole or indole) defined as substituent.
JP-A 09 216883 discloses pyridazinone derivatives which can be used to treat heart failure or high blood pressure. The pyridazinone derivatives described therein obligatorily have a pyrazolo[1,5-a]pyridine substituent in position 6, which is in turn substituted in position 2 by aryl, preferably phenyl. The pyridazinone ring itself is additionally substituted in position 2 by substituents such as hydrogen, lower alkyl or a heterocycle, while position 4 has substituents such as hydrogen, acyl, cyano, Heterocyclyl such as tetrazolyl, amino or a protected amino group. Where the substituent in position 4 is a heterocycle, it preferably has 3 to 8 ring members and is saturated. However, a heterocyclic group is not included in the preferred substituents in position 4 of the pyridazinone ring of the compounds disclosed in this document. Compounds as such explicitly disclosed in JP-A 09 215883 are no subject of the present invention.
Bicyclic heterocycles, having an inhibiting effect on aggregation, are described in EP-A 0 639 575. Therein, it is a general formula (I) disclosed having a bicyclus containing the substituent A, from which an indole-derivative can be derived having at least one additional nitrogen atom in the cycle which contains the substituent A. Furthermore, a pyridazinone derivative can theoretically be derived from the substituent B having in turn a multimembered substituent, which mandatorily contains a 1,4-cyclohexylen or 1,4-cyclohex-3-enylen group and a carbonyl group. Therefore, it is evident, that the compounds of the present invention are not disclosed by EP-A 0 639 575. Compounds such as explicitly disclosed by EP-A 0 639 575 are no subject of the present invention.
The documents EP-A 075 436, U.S. Pat. No. 4,734,415 and U.S. Pat. No. 4,353,905, both to Sircar et. al. describe pyridazinone derivatives as antihypertensive agents and as agents which increase cardiac contractibility. These pyridazinone derivatives have a phenyl residue at position 6 of the pyridazinone cycle, said phenyl residue is additionally substituted with a heterocycle containing at least one nitrogen atom. Whereas the pyridazinone derivatives described in the documents EP-A 075 436 and U.S. Pat. No. 4,353,905 do not have a substituent at position 4 of the pyridazinone cycle, those disclosed in U.S. Pat. No. 4,734,415 may have an amido group substituted with lower alkyl at this position. Compounds as such, explicitly disclosed by Sircar et. al. '415 are also not a subject of the present invention.
Thus, there exists a strong need for compounds that have an affinity for and have an inhibitory effect for GSK-3β and/or the phosphorylation of the tau-protein. The object of the present invention is to provide compounds that exhibit this ability.